Regulation of gene expression of hepatic drug metabolizing enzymes and transporters by the Toll-like receptor 2 ligand, lipoteichoic acid.
Expression of hepatic drug metabolizing enzymes (DMEs) is altered in infection and inflammation. However, the role of Gram+ve bacterial components and their receptor, Toll-like receptor (TLR) 2 in regulation of hepatic DMEs is unknown. Gene expression of DMEs is regulated by members of the nuclear receptor superfamily (PXR, CAR and RXRalpha). The TLR2 ligand, lipoteichoic acid (LTA) reduced RNA levels of CAR and its target genes, Cyp2b10, Cyp2a4 and Sultn in mouse liver ( approximately 60-80% reduction). Hepatic genes regulated by PXR and CAR, Cyp3a11 and Mrp2 were moderately reduced by LTA, along with approximately 50% reduction of PXR RNA and nuclear protein levels of RXRalpha. The effects of LTA were significantly attenuated by pre-treatment with the Kupffer cell inhibitor, gadolinium chloride, indicating that Kupffer cells contribute to LTA-mediated down-regulation of hepatic genes. These results indicate that treatment with Gram+ve bacterial components preferentially down-regulate CAR and its target genes in the liver.
Ghose
Romi
R
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 1441 Moursund Street, Houston, TX 77030, USA. rghose@uh.edu
Guo
Tao
T
Haque
Nadia
N
D000818:Animals; D018925:Chemokines / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D000077297:Pregnane X Receptor; D011494:Protein Kinases / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D015398:Signal Transduction; D013682:Teichoic Acids / Q000494:pharmacology*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*
C095218:Ccl9 protein, mouse; D018925:Chemokines; D019742:Chemokines, CC; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D052002:NF-kappa B p50 Subunit; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D047490:Retinoid X Receptor alpha; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; C073701:Nfkb1 protein, mouse; C009900:lipoteichoic acid; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D011494:Protein Kinases; D048670:MAP Kinase Kinase 4